ABSTRACT Infertility and spontaneous abortion (SAB) are important public health problems, affecting up to 20% of reproductive age couples. As couples increasingly postpone childbearing to the later reproductive years, many seek infertility treatment, which has relatively low success rates, costs an estimated $5 billion per year in the United States, and is associated with adverse pregnancy outcomes. Coping with the stress of infertility also exacts a measurable emotional toll in affected couples. Identifying modifiable risk factors for infertility and SAB is an important public health goal. Couples planning a pregnancy are notoriously difficult to recruit into research studies using traditional methods. We have shown that enrollment and follow-up of pre- conception couples via the internet in North America and Denmark is feasible, valid, and cost-efficient. We propose to harmonize data from three interrelated prospective preconception cohort studies in Denmark (Snart Gravid and Snart Foraeldre) and North America (PRESTO) to evaluate whether selected dietary factors and medications influence female and male fecundity, and SAB risk. In order to increase our statistical power to accomplish these aims, we will use our existing NICHD-supported web-based infrastructure to collect additional data from 6,000 females and 2,000 of their male partners. There is limited evidence on whether commonly-used medications, such as antibiotics, asthma drugs, antidepressants, and analgesics affect fertility and SAB, despite the potentially large attributable risk due to increasing use of medications among couples of reproductive age. In addition, there is a scarcity of research on dietary factors and reproduction from optimally-designed cohort studies of couples actively trying to conceive. Dietary factors of interest include high glycemic load/index, soy, and fish/seafood among females and red and processed meats, dairy, and trans-fatty acids among males. Most studies of TTP and SAB are retrospective in design and prone to misclassification, left truncation, and selection and recall biases. The few existing prospective studies of TTP and SAB are small and underpowered. The harmonization of large preconception cohorts with similar designs will provide excellent power to evaluate a broad range of hypotheses. Enrolling couples at the start of their pregnancy attempt can identify critical windows of exposure susceptibility. The use of social media and health-related websites for recruitment is innovative and extremely cost-effective relative to traditional methods. Inclusion of males is innovative because it allows for the assessment of individual and joint effects of exposures in both partners, and permits better control for confounding. Utilization of registry data will enable the collection of additional exposure and outcome data, data validation, identification of those lost to follow-up, and assessment of selection bias and generalizability. This will be the largest prospective preconception cohort study of modifiable risk factors for TTP and SAB to date. Findings from the proposed research are likely to have a large and sustained impact on the field and will result in actionable recommendations for couples to improve their fertility and lower their risk of SAB.